Multiple reports suggest that acceptance and use of opioid medicines for relief of chronic pain are increasing substantially, and that opioidergic medications (especially in high doses) and chronic pain each perturb neuroendocrine functions, particularly those of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes. In addition, numerous well-controlled analgesic trials attest to the high frequency and importance of the placebo effect in the treatment of pain. Several investigations suggest that neuroendocrine alterations underly the biology of the placebo effect. The latter observation is made more provocative by recent neuroimaging studies suggesting that placebo analgesia is associated with activation of similar anatomic components of the cortex as with bona fide analgesic intake. To date, however, there has been little systematic inquiry comparing the effects of chronic (versus acute) pain, conventional (versus high) dose opioid use and placebo administration on neureoendocrine function, pain symptomatology, or quality of life in a well-defined population of individuals with chronic musculoskeletal pain. Thus, the objectives of the current study are to evaluate, in middle-aged men with chronic musculoskeletal pain due to osetoarthritis (OA), the effects of chronic OA pain per se versus long-term opioid usage on neuroendocrine function (ACTH, cortisol, LH and testosterone secretion), pain symptomatology, mood and quality of life, and whether placebo analgesia results in similar, albeit soemwhat lesser, effects on on neuroendocrine function, pain symptomatology, mood and quality of life as those elicited by an opioid analgesic. [unreadable] [unreadable] To address these questions, we initiated a 2-part study. In part I, 16 opioid naive, non-obese men with chronic, moderate-severe osteoarthritis (OA) pain were comapred with 12 healthy men of similar ages and BMIs by assessing 12 hour overnight q 20 min blood sampling for measurements of ACTH, cortisol, LH and testosterone, as well as measures of pain symptomatology, mood and QOL.[unreadable] [unreadable] In part II, 36 opioid naive men with chronic OA pain (including the 16 OA patients noted above), all of whom will have undergone overnight hormone sampling and neuropsychological evaluations in Part I, will be randomized to one of three treatment groups: MS Contin (15-90 mg), placebo or ?standard treatment? with NSAID's. Doses of placebo and MS Contin will be escalated over 4 weeks in a similar fashion with two-week maintenance and 2 week taper. At the end of maintenance at 6 weeks, all patients will return for repeat 12 hour overnight frequent blood sampling and neuropsychological studies as in Part I. Two weeks later, patients will be asked to return for an outpatient assessment, after which they will be discharged to the care of their personal physicians. [unreadable] [unreadable] The primary endpoints of this study are measures of nocturnal ACTH, cortisol, LH, and testosterone secretion, whereas the secondary endpoints include AM SHBG, CBG, DHEAS, and CRP; 2h hour urine cortisol and catecholamines; and selected neurobehavioral indices of pain, mood and quality of life. Parts I and II of this study will provide novel information regarding the effects of chronic musculoskeletal pain, and treatment with opioids versus placebo, on selected neuroendocrine functions in men.[unreadable] [unreadable] Recruitment for this study began on 11/1/04, with considerable success to date. As of 9/15/06, 199 opioid naive OA patients have been phone screened, 34 completed out-patient screeening visits, 23 completed in-patient visit #1 (Part I), and 19 completed in-patient visit #2 (Part II). 43 healthy men were phone screened, 13 underwent screening visits, and 12 completed Part I.[unreadable] [unreadable] Part I of the study was completed in March, 2006. Data analysis revealed that neuroendocrine function was not significantly altered in otherwise healthy men with chronic musculoskeletal pain, suggesting that prior reports of such hormonal abnormalities may have resulted from the confounding effects of coexistent illness or medication use.[unreadable] [unreadable] A manuscript describing these results was accepted for publication in the Journal of Clinical Endocrinology and Metabolism.